Inhalation of chemotherapeutics has shown significant promise in humans in enhancing lung cancer response rates while reducing systemic toxicity. We h3^othesize that the efficacy and safety of inhaled chemo will be improved by an inhalable prolonged delivery strategy, since free drug is rapidly cleared from the airways by systemic absorption combined with mucus clearance mechanisms. Key to the potential of this effort is the recent development ofa mucus-penetrating nanoparticle (MPP) platform technology capable of providing delivery of controlled concentrations of drug locally to the lung airways over more sustained periods than previously possible viith conventional nanotechnologies. While conventional nanoparticles (CP) are easily immobilized in the outermost gel layer of mucus that is cleared rapidly from the lung by ciliary action, we discovered that particles coated with non-mucoadhesive polymers rapidly penetrate human mucus barriers. By penetrating the surface mucus layer, we hypothesize that MPP will; (1) avoid rapid elimination from the lung airways, (ii) provide prolonged delivery of chemotherapeutics locally and, thereby, (iii) significantly improve drug efficacy against SCLC, (iv) minimize systemic toxicity, and (v) provide enhanced efficacy when combined with systemic chemo regimens, where the systemic dose required may potentially be reduced. We will prepare biodegradable MPP loaded with frontline chemotherapeutic agents for SCLC, and evaluate them against unencapsulated drug and drug loaded in CP that are identical to the MPP, excluding the non-mucoadhesive coatings. In Aim 1, we will formulate MPP and cell-adhesive MPP and perform thorough characterization of the nanoparticles, including particle size, drug loading, release kinetics, and diffusion speeds in fresh undiluted human mucus and mouse tracheal mucus. In Aim 2, we will investigate nanoparticle retention in the lung airways of mice, and perform pharmacokinetic analysis of drugs released from MPP & cell-adhesive MPP as compared to CPan unencapsulated drug. In Aim 3, we will evaluate the in vivo safety and efficacy of drug-loaded MPP and cell-adhesive MPP compared to CP and unencapsulated drug in an orthotopic mouse SCLC model. GLP manufacture and safety/tox will be performed on the lead product by year 4 or 5 by the Validation Core in close consultation with the FDA.